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Benefits and disadvantages of hrt
The short version: HRT trades a real reduction in fracture, colorectal cancer, and all-cause mortality for a real increase in breast cancer, stroke, and blood clots. Whether that trade favors you depends on your age, your uterus, and your personal risk profile.
The best evidence comes from the Women's Health Initiative, the largest randomized trial ever done on this question. It found that estrogen-plus-progestin raised breast cancer risk by about 25% over 5 years (hazard ratio 1.25, 95% CI 1.07-1.46) and nearly doubled breast cancer death (HR 1.96) [1]. It also raised stroke (HR about 1.46) and venous thromboembolism nearly fourfold (from 2 per 1000 to 7 per 1000) [18, 26]. The harms were real.
But estrogen alone, in women who had already had a hysterectomy, went the other direction. Breast cancer risk fell by about 29% (HR 0.71) and breast cancer death fell by 63% (HR 0.37) [1]. Stroke risk still went up, but not as much. This is the most striking finding in the whole literature: the same hormone, delivered differently, produces opposite cancer effects.
The benefit side is substantial. HRT cuts hip and vertebral fractures by about 22% (from 111 per 1000 to 87 per 1000) [26]. It lowers colorectal cancer incidence by about 19% (adjusted HR 0.81) and colorectal cancer death by 37% (adjusted HR 0.63) [29]. A 2024 UK Biobank study found that ever-users had lower all-cause mortality (HR 0.92) and a biologically younger aging profile, especially if they started between ages 45 and 55 [28]. A Cochrane review found that younger women (starting under 60) had 6 fewer deaths per 1000 and 8 fewer heart disease cases, while older starters got no heart benefit [22].
| Outcome | Estrogen + progestin | Estrogen only (hysterectomy) |
|---|---|---|
| Breast cancer incidence | +25% (HR 1.25) [1] | -29% (HR 0.71) [1] |
| Breast cancer death | +96% (HR 1.96) [1] | -63% (HR 0.37) [1] |
| Stroke | +23% (RR 1.23) [18] | Similar increase |
| Venous thromboembolism | +174% (RR 2.74) [26] | +149% (RR 2.49) [14] |
| Hip fracture | -22% (RR 0.78) [26] | -22% |
| Colorectal cancer | -19% (HR 0.81) [29] | -19% |
| All-cause mortality | No change (RR 1.00) [26] | -8% (HR 0.92) [28] |
The evidence is thin in two ways. Most of these numbers come from one trial, the WHI, which used a specific formulation (conjugated equine estrogens plus medroxyprogesterone acetate) that is no longer the most common regimen. Transdermal estradiol (patches, gels) may carry lower clot risk than oral [21, 24], but the breast cancer data is weaker for these routes. The long-term follow-up beyond 10 years on different formulations is almost entirely observational, meaning it is open to the healthy-user bias: women who stay on HRT tend to be healthier to begin with.
My call: HRT is a real intervention with real upside and real downside. If you are under 60, have had a hysterectomy, and want relief from hot flashes and bone protection, estrogen alone is supported by strong trial evidence. If you have a uterus and need a progestin, the breast cancer risk is real and should not be dismissed, but the absolute risk is about 5 extra cases per 1000 women over 5 years, which many women accept for symptom relief. Starting after age 60 or for primary prevention of chronic disease has no net benefit and the USPSTF correctly recommends against it [25]. Confidence: moderate—the WHI is strong but dated, and the evidence on modern low-dose and transdermal regimens is not as solid.
Sources used 10
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Menopausal hormone therapy and breast cancer mortality: clinical implications
Combination menopausal hormone therapy with estrogen plus progestin increases breast cancer incidence and mortality and impairs detection, while estrogen alone reduces breast cancer incidence and mortality in women with prior hysterectomy, informing nuanced clinical use.
DOI: 10.1177/2042098614568300 -
Bias from depletion of susceptibles: the example of hormone replacement therapy and the risk of venous thromboembolism
This study investigates the association between hormone replacement therapy (HRT) and the risk of venous thromboembolism (VTE) in postmenopausal women, highlighting the phenomenon of depletion of susceptibles which affects the interpretation of risk based on duration of HRT use.
DOI: 10.1002/pds.4197 -
Update on the Cardiovascular Risks of Hormone Replacement Therapy
Systematic review of randomized trials shows hormone replacement therapy increases cardiovascular risk (venous thromboembolism and stroke) and does not protect against coronary heart disease, with absolute risk increases rising with age and potential differences by preparation a…
DOI: 10.2217/17455057.3.1.87 -
Hormone Therapy and Venous Thromboembolism Among Postmenopausal Women
The ESTHER study investigates the impact of the route of estrogen administration and progestogens on the risk of venous thromboembolism (VTE) among postmenopausal women, finding that oral estrogen increases VTE risk while transdermal estrogen does not, and that certain progestog…
DOI: 10.1161/CIRCULATIONAHA.106.642280 -
Hormone therapy and cardiovascular disease – are we back to the beginning?
This paper reviews the updated Cochrane Review on menopause hormone therapy (MHT) and its effects on cardiovascular disease, highlighting the differing impacts based on the timing of therapy initiation relative to menopause.
DOI: 10.3109/13697137.2015.1057958 -
Hormone therapy dose, formulation, route of delivery, and risk of cardiovascular events in women
This study investigates the relationship between different hormone therapy doses, formulations, and routes of delivery on cardiovascular disease outcomes in postmenopausal women, finding that various hormone therapy regimens are associated with similar rates of cardiovascular ev…
DOI: 10.1097/gme.0b013e31829a64f9 -
Hormone therapy should not be prescribed for primary prevention of chronic medical conditions in asymptomatic postmenopausal women
A USPSTF–commissioned systematic review and meta-analysis showing hormone therapy should not be used for primary prevention of chronic diseases in asymptomatic postmenopausal women, with estrogen-alone reducing some risks but increasing others and estrogen-plus-progestin increas…
DOI: 10.1136/bmjebm-2018-110930 -
Cochrane corner: long-term hormone therapy for perimenopausal and postmenopausal women
This study reviews the long-term effects of hormone therapy on mortality, cardiovascular outcomes, cancer, gallbladder disease, fractures, and cognitive function in perimenopausal and postmenopausal women, highlighting both risks and benefits associated with different types of h…
DOI: 10.1136/heartjnl-2017-311583 -
Hormone Therapy and Biological Aging in Postmenopausal Women
Historical hormone therapy use in postmenopausal women is linked to a biologically younger aging profile (smaller phenotypic age discrepancy), with stronger effects in lower-SES groups, and this discrepancy partially mediates reduced mortality.
DOI: 10.1001/jamanetworkopen.2024.30839 -
Hormone Replacement Therapy and Colorectal Cancer Incidence and Mortality in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial
This study uses secondary analysis of the PLCO trial to show that hormone replacement therapy in postmenopausal women is associated with reduced colorectal cancer incidence and mortality, with stronger benefits among current users after adjustment for demographic and clinical fa…
DOI: 10.1016/j.clcc.2018.01.003